Acetylcholinesterase inhibitors are agents which inhibit the cholinesterase enzyme from breaking down acetylcholine, thereby increasing both the level and duration of action of the neurotransmitter acetylcholine. Examples of reversible inhibitors of acetylcholinesterase include organophosphates; carbamates; phenanthrene derivatives; piperidine derivatives; tacrine, edrophonium, huperzine A and ladostigil.
Acetylcholinesterase inhibitors are indicated for the management of mild to moderate Alzheimer's disease, which is associated with significant losses in cholinergic neurons and decreased concentrations of acetylcholine, which is significantly involved in learning and memory processes. Acetylcholinesterase inhibitors commonly used in the treatment of Alzheimer's disease include donepezil, rivastigmine and galantamine.
Donepezil ((±)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-one hydrochloride), a piperidine derivative, is a centrally acting reversible acetylcholinesterase inhibitor, used mainly in the treatment of Alzheimer's disease, where it is used to increase cortical acetylcholine. It has an oral bioavailability of about 100%, and easily crosses the blood-brain barrier.
Donepezil is both excreted in the urine intact and extensively metabolized to four major metabolites, two of which are known to be active, and a number of minor metabolites, not all of which have been identified. Donepezil is metabolized by CYP 450 isoenzymes 2D6 and 3A4 and undergoes glucuronidation.
US 20060159753 teaches a sustained release formulation comprising a basic drug, which may be donepezil, and at least one enteric polymer.
U.S. Pat. No. 4,792,452 discloses a controlled-release formulation for a pharmaceutical of basic character comprising a pH-dependent polymer and a pH-independent hydrocarbon gelling agent.
U.S. Pat. No. 6,287,599 teaches sustained release pharmaceutical dosage forms comprising at least one non-pH dependent sustained release agent and at least one pH dependent agent.
US 20060280789 and US 20070129402 teach matrix-type sustained release formulations of basic drugs, including acetylcholinesterase inhibitors, such as donepezil, comprising at least one enteric polymer and optionally at least one water-insoluble polymer.
WO 07/036,952 teaches a sustained release formulation comprising a combination of a non-swelling pH dependent release retardant and a non swelling pH independent release retardant.
Donepezil hydrochloride is currently marketed for oral administration under the trade names ARICPEPT®, by Eisai, in the form of film-coated tablets and orally-disintegrating tablets, comprising 5 or 10 mg of the active ingredient. The tablets provide immediate release of donepezil and are generally administered once a day. Peak plasma concentrations are reached in 3 to 4 hours, causing a sharp spike in the patient's blood plasma levels. The initial spike in blood plasma levels may cause undesirable side effects in patients, such as anxiety, nightmares, insomnia, and/or gastrointestinal problems (e.g., nausea, emesis, diarrhea).